Reactivation of the fetal Gamma globin genes might compensate for deficient Beta globin synthesis in patients with severe Beta thalassemia, thereby making erythropoiesis more effective and reducing the need for transfusions. 5-Azacytidine (5-AzaC) has been shown to stimulate Hb F production in anemic baboons. This protocol was designed to determine whether 5-Aza would have a similar effect on fetal hemoglobin production in humans. Patients are given a continuous intravenous infusion of 5-AzaC at a dose of 2 mg/kg/day; this dose was found to cause minimal aspirates were analyzed for globin protein synthetic rates, mRNA concentrations, and the methylation status of DNA in the globin gene region. Two patients have been studied thus far. The first is a patient with Beta thalassemia and severe iron overload. Gamma globin synthesis increased seven-fold in this patient, normalizing the previously unbalanced globin synthetic ratio, the absolute reticulocyte count and hemoglobin concentration therefore increased. Hypomethylation of DNA near the epsilon and gamma globin genes was directly demonstrated. The Gamma globin genes were expressed at a level of 7,000 copies per cell, in contrast to 15 copies of epsilon globin mRNA per cell. A second patient with sickle cell disease has been treated; preliminary results suggest a similar augmentation of Hb F production and markedly decreased "sickling" after therapy.